Methods for activating immune cells

Abstract

Provided herein are methods for activating an immune cell in a subject. In some embodiments, the methods comprise passing an immune cell from a subject through an immune modulating chamber comprising a tumor cell, thereby activating the immune cell, and returning the activated immune cell to the subject. In some embodiments, the methods further comprise isolating an immune cell-containing portion of a sample and passing the immune cell-containing portion through the immune modulating chamber. Methods of treating cancer and methods of inducing an immune response against a tumor are also provided herein.

What is claimed is: 
     
         1 . A method for activating an immune cell in a subject, the method comprising:
 (a) passing an immune cell from the subject through an immune modulating chamber, wherein the immune modulating chamber comprises a solid support and (i) a tumor cell, (ii) a pro-immunogenic factor, and (iii) a stromal component that are restrained on the solid support within the immune modulating chamber, thereby exposing the immune cell to the tumor cell, the pro-immunogenic factor, and the stromal component and activating the immune cell, and wherein the immune modulating chamber comprises an inlet port and/or an outlet port in fluid communication with the subject's vascular system, peritoneal cavity, pleural cavity, or cerebrospinal fluid (CSF); and   (b) returning the activated immune cell to the subject.   
     
     
         2 . The method of  claim 1 , wherein the method is performed ex vivo. 
     
     
         3 . The method of  claim 1 , wherein the method increases an autologous immune response in the subject. 
     
     
         4 . The method of  claim 1 , wherein the method reduces or eliminates an adverse effect of a systemic therapy in the subject. 
     
     
         5 . The method of  claim 1 , wherein the immune cell is a leukocyte or peripheral blood mononuclear cell (PBMC). 
     
     
         6 . The method of  claim 1 , wherein the immune cell is contained within a whole blood sample that is obtained from the subject. 
     
     
         7 . The method of  claim 6 , wherein the whole blood sample is passed through the immune modulating chamber. 
     
     
         8 . The method of  claim 6 , wherein an immune cell-containing portion is isolated from the whole blood sample, and the immune cell-containing portion of the whole blood sample is passed through the immune modulating chamber. 
     
     
         9 . The method of  claim 8 , wherein the immune cell-containing portion of the whole blood sample is isolated using a filtration method. 
     
     
         10 . The method of  claim 8 , wherein the immune cell-containing portion of the whole blood sample is isolated using apheresis. 
     
     
         11 . The method of  claim 8 , wherein the immune cell-containing portion of the whole blood sample is isolated by passing the whole blood sample through an isolation device that is in fluid communication with the immune modulating chamber. 
     
     
         12 . The method of  claim 8 , wherein an immune inhibition factor and/or a factor that has an adverse effect on the subject are removed from the immune cell-containing portion and/or a non-immune cell-containing portion of the whole blood sample before the immune cell-containing portion and/or the non-immune cell-containing portion of the whole blood sample are returned to the subject. 
     
     
         13 . The method of  claim 1 , wherein the inlet and/or outlet port are in fluid communication with the subject's venous system. 
     
     
         14 . The method of  claim 1 , wherein the inlet and/or outlet port are in fluid communication with the subject's arterial system. 
     
     
         15 . The method of  claim 1 , wherein the tumor cell is a circulating tumor cell (CTC). 
     
     
         16 . The method of  claim 1 , wherein the tumor cell comprises a plurality of tumor cells. 
     
     
         17 . The method of  claim 1 , wherein the tumor cell is obtained from a biopsy, a fine needle aspirate (FNA), a surgical resection, a blood sample, a pleural effusion sample, a peritoneal effusion sample, a CSF sample, or a combination thereof. 
     
     
         18 . The method of  claim 1 , wherein the tumor cell comprises an autologous tumor cell. 
     
     
         19 . The method of  claim 1 , wherein the tumor cell comprises an allogeneic tumor cell. 
     
     
         20 . The method of  claim 1 , wherein the tumor cell is introduced into the immune modulating chamber before the immune cell is passed through the immune modulating chamber. 
     
     
         21 . The method of  claim 1 , wherein the tumor cell is introduced into the immune modulating chamber concurrently with the immune cell. 
     
     
         22 . The method of  claim 21 , wherein the tumor cell is contained within a whole blood sample or immune cell-containing portion thereof, and becomes restrained on the solid support within the immune modulating chamber as the blood sample or immune cell-containing portion thereof passes through the immune modulating chamber. 
     
     
         23 . The method of  claim 1 , wherein the tumor cell is restrained on the solid support by a capture moiety. 
     
     
         24 . The method of method of  claim 23 , wherein the capture moiety also promotes tumor cell proliferation. 
     
     
         25 . The method of  claim 23 , wherein the capture moiety is selected from the group consisting of an antibody, a cell adhesion molecule, and a combination thereof. 
     
     
         26 . The method of  claim 25 , wherein the antibody is an antibody that binds to epithelial cell adhesion molecule (EpCAM), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), MUC1, CD44, HER2, HER3, FGFR1, FGFR2, FGFR3, FGFR4, IGF1R, c-Met, EGFR, PD-L1, or a combination thereof. 
     
     
         27 . The method of  claim 25 , wherein the cell adhesion molecule is selected from the group consisting of a selectin, an integrin, vascular cell adhesion molecule 1 (VCAM1), and a combination thereof. 
     
     
         28 . The method of  claim 27 , wherein the selectin is selected from the group consisting of E-selectin, L-selectin, and a combination thereof. 
     
     
         29 . The method of  claim 1 , wherein the immune modulating chamber further comprises an anti-immune inhibition factor. 
     
     
         30 . The method of  claim 1 , wherein the pro-immunogenic factor is selected from the group consisting of interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin 17 (IL-17), interleukin-18 (IL-18), interleukin 22 (IL-22), C—X—C chemokine receptor type 3 (CXCR3), interferon betta (IFNβ), interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), granulocyte-macrophage colony-stimulating factor (GM-CSF), and a combination thereof. 
     
     
         31 . The method of  claim 1 , wherein the pro-immunogenic factor is IL-2. 
     
     
         32 . The method of  claim 29 , wherein the anti-immune inhibition factor is selected from the group consisting of an immune checkpoint inhibitor, an indoleamine 2,3-dioxygnease (IDO) inhibitor, and a combination thereof. 
     
     
         33 . The method of  claim 32 , wherein the immune checkpoint inhibitor inhibits programmed cell death 1 ligand  1  (PDL1), programmed cell death protein 1 (PD1), cytotoxic T lymphocyte associated protein 4 (CTLA4), T cell immunoglobulin 3 (TIM3), lymphocyte activation gene 3 (LAG3), V-domain Ig suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), or a combination thereof. 
     
     
         34 . The method of  claim 1 , wherein the immune modulating chamber further comprises a subject-specific mutated peptide. 
     
     
         35 . The method of  claim 34 , wherein the subject-specific mutated peptide is selected from the group consisting of EGFRvIII peptide, p95HER2 peptide, an EGFR peptide comprising an activating mutation, and a combination thereof. 
     
     
         36 . The method of  claim 23 , wherein the capture moiety is attached to the solid support. 
     
     
         37 . The method of  claim 1 , wherein the solid support comprises an interior surface of the immune modulating chamber or a support structure that is in contact with an interior surface of the immune modulating chamber, and optionally further comprises a magnetic composition. 
     
     
         38 . The method of  claim 37 , wherein the support structure comprises a matrix. 
     
     
         39 . The method of  claim 36 , wherein the capture moiety is covalently attached to the solid support. 
     
     
         40 . The method of  claim 36 , wherein the capture moiety is magnetically attached to the solid support. 
     
     
         41 . The method of  claim 40 , wherein the capture moiety;
 comprises a magnetic particle.   
     
     
         42 . The method of  claim 40 , wherein the solid support comprises a magnetic composition and wherein the capture moiety is magnetically attached to the magnetic composition. 
     
     
         43 . The method of  claim 40 , wherein an electromagnetic field that is external to the immune modulating chamber is used to magnetically attach the capture moiety to the solid support. 
     
     
         44 . The method of  claim 1 , wherein the tumor cell is induced to undergo apoptosis by exposure to an oncolytic virus, radiation, and/or a chemotherapeutic agent. 
     
     
         45 . The method of  claim 1 , wherein the subject is administered a chimeric antigen receptor T-cell. 
     
     
         46 . The method of  claim 1 , wherein the immune modulating chamber further comprises a flow regulator and/or a pump. 
     
     
         47 . The method of  claim 46 , wherein the flow regulator and/or the pump are used to adjust the rate at which the immune cell passes through the immune modulating chamber. 
     
     
         48 . The method of  claim 46 , wherein the availability of oxygen inside the immune modulating chamber is controlled by using the flow regulator and/or the pump to adjust the flow rate of whole blood through the immune modulating chamber and/or by adjusting the number or density of red blood cells passing through the immune modulating chamber. 
     
     
         49 . The method of  claim 1 , wherein multiple immune modulating chambers are used. 
     
     
         50 . The method of  claim 49 , wherein the multiple immune modulating chambers are each in fluid communication with each other. 
     
     
         51 . The method of  claim 49 , wherein each of the multiple immune modulating chambers comprises a different tumor cell. 
     
     
         52 . The method of  claim 1 , wherein the tumor cell is removed from the immune modulating chamber after the immune cell has passed through the immune modulating chamber, and the presence or level of one or more biomarkers in the tumor cell is detected. 
     
     
         53 . The method of  claim 52 , wherein the presence or level of the one or more biomarkers is used to provide a diagnosis to the subject and/or select a treatment for a disease in the subject. 
     
     
         54 . A method for treating cancer in a subject, the method comprising activating an immune cell and returning the activated immune cell to the subject according to the method of  claim 1 . 
     
     
         55 . The method of  claim 54 , wherein the cancer comprises a solid tumor. 
     
     
         56 . The method of  claim 54 , wherein the cancer is selected from the group consisting of lung cancer, brain cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, melanoma, a sarcoma, and a combination thereof. 
     
     
         57 . A method for inducing an immune response against a tumor in a subject, the method comprising activating an immune cell and returning the activated immune cell to the subject according to the method of  claim 1 . 
     
     
         58 . The method of  claim 57 , wherein the tumor comprises the same type of tumor cell that is restrained on the solid support within the immune modulating chamber. 
     
     
         59 . The method of  claim 57 , wherein the tumor is a solid tumor. 
     
     
         60 . The method of  claim 57 , wherein the tumor is from a cancer selected from the group consisting of lung cancer, brain cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, melanoma, a sarcoma, and a combination thereof.